PROJECT SUMMARY An effective cure for Parkinson's disease (PD) is an unmet need, since current treatments have proved ineffective to slow down or reverse the progression of the disease. The exact mechanisms of the selective nigrostriatal cell loss in PD are still poorly understood, but there is an increasing consensus that oxidative stress and neuro-inflammation play a critical role. In this regard, new pharmacological strategies, based on the activation of Nrf2-dependent antioxidant, tissue-repair responses, the inhibition of pro-inflammatory NF-kB-dependent cytokine and adhesion molecule expression, and NADPH oxidase-2 (NOX-2) activity, have shown promising results in PD therapy. The new drug candidate 10-nitro-oleic acid (10-NO2-OA) displays tissue- protective and anti-inflammatory actions in multiple preclinical models, has cleared 5 Phase 1 human trials in 107 subjects, and is now in Phase II studies related to the treatment of chronic pulmonary and renal diseases. Notably, we have just discovered that 10-NO2-OA readily cross the blood-brain barrier. From this insight, it is now hypothesized that 10-NO2-OA accesses the nigrostriatal region of the brain and will inhibit oxidative stress and neurodegeneration in PD through modulation of Nrf2- and NF-kB-dependent gene expression and inhibition of pro- inflammatory NADPH oxidase-2 (Nox-2) activity. Then, we propose to study preclinical models to define the efficacy of 10-NO2-OA in limiting the pathogenesis of PD. The rationale for this project is that the establishment of therapeutic 10-NO2-OA concentrations in the brain will promote beneficial pleiotropic tissue-protective responses, thus representing a safe and effective drug strategy to prevent the progression of a multi-factorial disease such as PD. The goals of this proposal are: 1) Define the neuroprotective potential of 10-NO2-OA through the modulation of Nrf2- and NF-kB-dependent gene expression and inhibition of Nox-2 activity in an in vitro model of PD, 2) Evaluate the PK of 10-NO2-OA in the midbrain and its neuroprotective effects in a rotenone model of PD in rat. Successful completion of the proposed research plan can have a significant positive impact by revealing a new pharmacological strategy to alleviate the economic and clinical burden of PD. .